rs757247746

Variant names:

• chr8-6406682-C-G
• rs757247746
• NM_024596.5:c.15C>G

Your query was ambiguous. Multiple possible variants found:

• chr8-6406682-C-G
• chr8-6406682-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_024596.5(MCPH1):​c.15C>G​(p.Ile5Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000822 in 1,459,836 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: MCPH1 NM_024596.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.174

Genes affected

MCPH1 (HGNC:6954): (microcephalin 1) This gene encodes a DNA damage response protein. The encoded protein may play a role in G2/M checkpoint arrest via maintenance of inhibitory phosphorylation of cyclin-dependent kinase 1. Mutations in this gene have been associated with primary autosomal recessive microcephaly 1 and premature chromosome condensation syndrome. Alternatively spliced transcript variants have been described. [provided by RefSeq, Feb 2010]

MCPH1-DT (HGNC:55599): (MCPH1 divergent transcript)

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16007867).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MCPH1	NM_024596.5	c.15C>G	p.Ile5Met	missense_variant	Exon 1 of 14	ENST00000344683.10	NP_078872.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MCPH1	ENST00000344683.10	c.15C>G	p.Ile5Met	missense_variant	Exon 1 of 14	1	NM_024596.5	ENSP00000342924.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000822 AC: 12 AN: 1459836 Hom.: 0 Cov.: 33 AF XY: 0.00000964 AC XY: 7 AN XY: 726208

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000108

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	16
DANN	Benign	0.80
DEOGEN2	Benign	0.22	T;.;.
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.067	N
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.16	T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.93	L;L;L
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.83	N;N;N
REVEL	Benign	0.090
Sift	Uncertain	0.021	D;D;D
Sift4G	Uncertain	0.053	T;T;T
Polyphen		0.036	B;.;.
Vest4		0.19
MutPred		0.55		Gain of disorder (P = 0.0363);Gain of disorder (P = 0.0363);Gain of disorder (P = 0.0363);
MVP		0.52
ClinPred		0.13	T
GERP RS		-1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.34
gMVP		0.46

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs757247746; hg19: chr8-6264203;